title: Noonan syndrome and clinically related disorders.
abstract: Noonan syndrome is a relatively common, clinically variable developmental disorder. Cardinal features include postnatally reduced growth, distinctive facial dysmorphism, congenital heart defects and hypertrophic cardiomyopathy, variable cognitive deficit and skeletal, ectodermal and hematologic anomalies. Noonan syndrome is transmitted as an autosomal dominant trait, and is genetically heterogeneous. So far, heterozygous mutations in nine genes (PTPN11, SOS1, KRAS, NRAS, RAF1, BRAF, SHOC2, MEK1 and CBL) have been documented to underlie this disorder or clinically related phenotypes. Based on these recent discoveries, the diagnosis can now be confirmed molecularly in approximately 75% of affected individuals. Affected genes encode for proteins participating in the RAS-mitogen-activated protein kinases (MAPK) signal transduction pathway, which is implicated in several developmental processes controlling morphology determination, organogenesis, synaptic plasticity and growth. Here, we provide an overview of clinical aspects of this disorder and closely related conditions, the molecular mechanisms underlying pathogenesis, and major genotype-phenotype correlations.
authors.affiliation: Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome, Italy. mtartaglia@iss.it
authors.forename: Marco
authors.initials: M
authors.lastname: Tartaglia
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Gelb
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
mesh_terms: D000293:Adolescent; D002648:Child; D056685:Costello Syndrome / Q000175:diagnosis / Q000235:genetics; D004476:Ectodermal Dysplasia / Q000175:diagnosis / Q000235:genetics; D019066:Facies; D005183:Failure to Thrive / Q000175:diagnosis / Q000235:genetics; D006330:Heart Defects, Congenital / Q000175:diagnosis / Q000235:genetics; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D044542:LEOPARD Syndrome / Q000175:diagnosis / Q000235:genetics; D058247:Loose Anagen Hair Syndrome / Q000175:diagnosis / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics; D009456:Neurofibromatosis 1 / Q000235:genetics; D009634:Noonan Syndrome / Q000175:diagnosis / Q000235:genetics*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics; D020837:SOS1 Protein / Q000235:genetics
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C112913:SHOC2 protein, human; D020837:SOS1 Protein; D050721:Proto-Oncogene Proteins c-cbl; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C067419:CBL protein, human